Amines



United States Patent F AMINES Richard V. Heinzelman, Kalamazoo Township,Kalamazoo County, and Brooke D. Aspergren, Kalamazoo,

Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michigan No Drawing. Application November 12, 1952, Serial No.320,125

Claims. (Cl. 260326.5)

subsequent unsuccessful attcmpts of other investigators to preparetertiary aminoketones by the use of the Voigt reaction. For example,Cowper and Stevens, J. Chem. Soc., 347 (1940), were unable to condensemethylaniline with a benzoin compound even under extreme reactionconditions. More recently, Lutz, Freek and Murphy, I. Am. Chem. Soc.,70, 2015, (1948), employed the Voigt reaction to prepare secondaryaminoketones but had. to resort to other procedures to prepare tertiaryamino ketones. Evidence lending further support to the foregoing isofiered by applicants own unsuccessful attempts to condense benzoin withdicthylamine using the reaction conditions set forth by Voigt, in whichcase the end product of the reaction was the unreacted benzoin.

' It is an object of the present invention to prepare tertiary cyclicN-desylamines by a new and novel process. Another object of thisinvention is to prepare tertiary cyclic' N-desylamines in substantiallyhigh yields by a simple, direct and relatively economical procedure;Other objects and featuresof the invention will be apparent to thoseskilled in the art to which this invention pertains.

It has now been discovered thattertiary cyclic N-desylamines canbeprepared by reacting, preferably at elevated temperatures, a cyclicsecondary amine wherein the amino nitrogen atom is a member of the ring,such as, for example, a pyrrolidine, piperidine, morpholinc, hy-'droquinoline, or the like, with a selected aromatic ketone such as, forexample, benzoin, dimethoxybenzoin, diethoxybenzoin, dipropoxybenzoin,methoxyethoxybenzoin, methoxypropoxybenzoin, or the like, preferably inthe presence of an acidic condensing agent such as concentratedhydrochloric acid, zinc chloride, phosphorus trichloride, or phosphoruspentoxide, the latter being especially preferred. The tertiary cyclicN-desylamine obtained by this procedure may be isolated from thereaction mixture by the addition of a water-immiscible organic solventsuch as diethylether, benzene, ethyl acetate, or the like, extractingthe resulting solution with a dilute aqueous-acid solution, treatingtheaqueous-acid extract thus-obtained with an alkali, and extracting thedesired tertiary cyclic aminoketone with ether. The ether extract isthen dried and .the solvent removed therefrom by. distillation to obtainthe desired tertiary cyclic N-desylamine. Similarly, by reacting benzoinwith a substituted cyclic secondary amine wherein the amino nitrogenatom is amember of the ring, such as, for example, Z-methylpyrrolidine,2,3-dimethylpyrrolidine, 2-ethylpiperidine, 2- methylmo'rpholine,2-methyldecahydroquinoline, or the like, the corresponding tertiarycyclic N-desylamine, i. e.,

N-desyl-Z-mthylpyfiolidine, N desyl-2,3-dimethylpy'i' rolidine,N-desyl-Z-ethylpiperidine, N-desyl-2-methylmorpholine,N-desYl-Z-methyldecahydrbquinoline, or the like, is obtained.

The compounds produced by the method of the present invention arerepresented by the following formula:

R as

wherein R is a tertiary cyclic amine radical connected to the carbonatom of the above-indicated formula by a ring nitrogen atom and R1 is amember selected from the group consisting of hydrogen and an alkoxyradical,

the diphenylethyl ketone radical, attached to the radical identified asR, being referred to herein as the desyl radireduction to 'a hydroxygroup of'the keto group in the corresponding N-desylpyrrolidine,N-desylpiperidine, or

the like, as with lithium aluminum hydride.

The following examples are illustrative of the process and products ofthis invention and are not to be construed as limiting.

Example 1.N-(para,para'-dimethoxydesyl) pyrrolidine A mixture of 27.2grams of para-anisoin, 7.1 grams of pyrrolidine, and two grams ofphosphorus pentoxidewas heated at about 100 degrees'centigrade for fourhours. After cooling the reaction mixture, 250 milliliters of aone-normal hydrochloric acid solution was added thereto. The acidextract containing the thus-formed N-(para,para-dimethoxydesyl)-pyrrolidine was decolorized with activatedcarbon, made, alkaline with a dilute aqueous sodium hydroxide solution,and the mixture extracted twice with ZOO-milliliter portions ofdiethylether. The ether extracts were combined, dried over anhydroussodium sulfate and the solvent removed therefrom by distillation toobtain N-(para,para-dimethoxydesyl)-pyrrolidine.

To convert the free base to its hydrochloride, ten grams of thethus-produced N- (para,para'-dimethoxydesyl)*pyrrolidine was dissolvedin about 200 milliliters of ether and mixed with fifty milliliters of anethanolic solution of hydrogen chloride. separated by decantation andrecrystallized from a mixture of ethanol and ether.(para,para'-dimethoxydesyl) pyrrolidine hydrochloride melted at 225 to227 degrees centigrade, with decomposi tion.

Anal.Calc. for C20H24C1NO3: C, 66.38; H, 6.69 ;'Cl,

Found: C, 66.53; H, 6.71; Cl, 9.76;

Example 2.N-(0rtho,ortho-dimethoxydesyl)-pyrrolidine A mixture of 27.2grams of ortho-anisoin, 7.1 grams of pyrrolidine, and two grams ofphosphorus pentoxide was The semi-solid which formed was Thesubstantially pure N-i gradew-ith stirring for five hours.

heate'd'at about 100 degrees centigrade forthr'eehours,

cooled, and then extracted with about 200 milliliters of ether.-..The-,-.ether; extract 'v'vas, washed twicefiwith 200;, millil er,portions of water and ;then extracted-,with 200 milliliters, of aone-normalgaqueous hydrochloric acid seiution; 'The resultingaqueous-acid extract Wasmade.

alkaline with a dilute aqueous sodium hydroxide solution and extracted[with .2 milliliters of ether The-ether extract was dried over anhydroussodium sulfate and the solvent removed therefrom by distillation toobtain N- (ortho,ortho'-dimethoxydesyl)-pyrrolidine in solid form.

To convert the free base; to its hydrochloride, ten grams of thethus-produced N-'(-ortho,ortho-dimethoxydesyl)- I pyrr'olidine wasdissolved in about 200 milliliters of ethyl acetate and mixed with-fiftymilliliters of an et-hanolic solution of hydrogen chloride. TheN-(orthoprtho dimethoxydesyl) -py=rr'olidinehydrochloride thus-formedwas recovered "from the alcoholic solution in the form of a semi-solid.r

1' The N-(ortho,ortho-d-irnethoxydesylj pyrrolidine hydrochloridethus-obtained was converted'to the free base byt'reatment with sodiumhydroxide, extracted with ether, dried, and then reduced with lithiumaluminum hydride to obtain-the corresponding alcohol,a,/8-di-(ortho-methoxy-,

phenylyfi-(pyrrolidyl-l)=ethanol. On treating the thusobtainedage-di-(ortho-methoxyphenyl)-/3-(pyrrolidyl-1)- ethanol with anethanolic solu-tionof hydro-gen chloride, the correspondinga,fl-di-(ortho-methoxyphenyl)-fi-(pyrrolidyl-ll-eth-anol hydrochloride,melting at 227 to 228 degreesrcentigrade, is obtained.

* Anal.Calc. for CzoHzeClNOa: C, 66.01; H, 7.20; CI, 9 .74; N, 3.85.Found: C, 66.26; H, 6.96; Cl,9.68; N, 4.10.

Example 3 .-N-(meta,mttf-dimethoxydesyl) -pyrrolidirie Followin'gtheprocedure set forth in Example lsupra except for the substitutionofpara-anisonin by meta-anisoin, N-(meta, meta-dimethoxydesyl)-pyrrolidineis obtained.

' Example 4.--N-desylpyrr0lidine for example, N-desylpyrrolidinesulfate, N-desylpyrrolidine benzoate, or the like.

Example 5.N-desyl-2-methylpyl rolidine ,j- Eel-lowing the procedure setforth in Example 1 supra except for the substitution of pyrrolidine byZ-methylpyrrolidine, N-desyl-2-rnethylpyrrolidine is obtained.

Example 6.N-desylpiperidin e A. mixture of 106.2 grams (0.5 mole) ofbenzoin, 46.8 grams (0.55 mole) of piperidine, and five grams ofphosphoruspentoxide was heated at about 100 degrees centi- To thereaction mixturewas added 200 milliliters of benzene and 200milliiitersof an aqueous solution containing 12.5 percentby weight ofhydrochloric acid. Thirty-five grams of benzoin Wereremoved byfiltration from the resulting organic layer, the latter then beingdiscarded. The aqueous-acid solution was made alkaline by the additionof a dilute sodium hydroxide solution, thereby precipitating 53.5

grams of N-desylpiperidine, a yellow-white solid which melted at 80 to84 degrees centigrade.

AnaL C-alc. for CisHziNOz C, 81.68; H, 7 .57; N, 5.01."

Found:,C, 81.85.; H, 7.64; N, 5.02.

3T0 convert the...=free base, to itsihydrochloride, the thusproducedN-desylpiperidine was dissolved in 150 milliliters of ethylacetateandm-ixed with a slight excess of an ethanolic solution of hydrogenchloride. The resulting gummy precipitate was converted to a solid byrubbing with a glass rod and recrystallized from an ethanol-ethermixture to obtain N-desylpipe ridine hydrochloride having a meltingpoint of 236 to 2 38-d'egrees centigrade. V I

Anal.Calc. for C19H22 ClNO: C, 72.25; H, 7.02; Cl, 11.23; N, 4.43.Found: C, 72.37; H, 7.17; Cl, 11.03;'N,' 4.72.

Similarly, by reacting N-desylpiperidine with alcoholic solutions ofother selected acids such as, for example, sulfuric acid, .berizoicacid,;or the like, the correspondingacid addition salts ofN-desylpiperidineyare obtained such as, for example, N- desylpiperidinesulfate, N-desylpiperidine benz'oate, or the like.

. I Example 7. J\l-desylmorpholine phor'us pentoxidewas heated at aboutdegreescen'tigrade for five hours. The resulting slurry was cooled, .250

milliliters of-ether added to dissolve the solids, and the desiredproduct, N-desylmorpholine, extracted by the addition of 250 millilitersof an aqueous hydrochloric acid solution containinglten percent byweight of hydrochloric acid; The acid-extract containingN-desylmorpholine was made alkaline with adilute aqueous sodiumhydroxide solution and the free base extracted with ether. The etherextract-containing N-desylmorpholine was dried over anhydrous sodiumsulfate and the solvent removed therefrom by distillation to obtain thedesired N-desylmorpholine.

To convert the free base to its hydrochloric, the thusproduced-Ndesylmorpholine-Was dissolved in 250 milliliters of ethyl acetate andmixed with a slight excess of an ethanolic= solution of hydrogenchlorideto obtain the desired N-desylmorpholine hydrochloride, having a meltingpoint of 198 to 200 degreescen-tig-rade.

Example 8. N desyldecahydroq'uinoline Bye-reacting a mixture.of'106.-12grams (0.5 mole) of benzoin, 7.3.3.-grams (0.55 mole) ofdecahydroquinoline, and live grams of phosphorus pentoxide in the mannerdescribed in Example 1 supra, Ndesyldecahydroquinoline is obtained.

Similarly, by reacting a mixture of benzoin and-tetrahydroquinoline inthe presence of phosphorus pentoxide, the corresponding.N-desyltetrahydroquinoline is obtained.

Following, theprocedure set forth above, other tertiary cyclic.N-desylamines may be prepared such as, for example, N .-.:(para,paradiethoxydesyl) -,pyrrolidine, N.-. (ortho,ortho' diethoxydesyl)pyrrolidine, N-(meta, metaf-diethoxydesyl)apyrrolidine,N-(para,para'-dipropoxydesyl -pyrrolidine, N- ortho,para'-dipropoxydesyl pyrrolidine, N- (p ara,pa ra-dibutoxydesyl-) -pyrrolidine, N-(para-methoxy-para'-ethoxydesyl)-pyrrolidine, N-(para', para.diamyloxydesyl) pyrrolidine, N (para',para' dihexyloxydesyl)pyrroli'dine, N-(para,para'-diheptyloxydesyl) pyrrolidine, N (para, paradioctyloxydesyl) pyrrol-idine, N- (pa-na,para-diethoxydesyl -piperidine,1N (ortho,orthot-diethoxydesyl)-piperidine, N-(meta,metadiethoxydesyl)piperidine, N (para,paira dipropoxydesyl) piperidine, -N (ortho,para'dipropoxydesyD- piperidine, -N (para,p ara dibutoxydesyl)-piperidine',N- (par-a methoxy para ethoxydesyl) piperidine, N-(para,para'-diamyloxydesyl) piperidinc, N-(para,para-dihexyloxydesyl)piperidine, N- (par-a,para' -;diheptyloxydesyl piperidine, N(p-ara,p'ara dioctyloxydesyD- piperidine, N-I(par-a,para-diethoxydesyl)-morpholine, N- (ortho,ortho-diethoxydesyl)-morph0line, N-(meta,meta'- diethoxydesyl) morpholine, N(para,pa-ra' dipropoxydesyl) morpholine, N (para,para' dibut'oxydesyD-morpholine, N- (para methoxy para ethox-ydesyl)- morpholine, N(ortho,ortho' diethoxydesyl) decahydroquinoline, N:- (meta-,meta-..diethoxyde'syl)- decahydroquinoline, N (para,para' dipropoxydesyl)decalhydroquinoline, N (para,para dibutoxydesyl) decahydroquinoline, N(para methoxy para ethoxydesyl) decahydroquinoline, acid addition saltsof the [foregoing free amine bases, and the like.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeoftheappended claims.

We claim: v

6 1. A process for the preparation of tertiary N-desylamines of theformula:

E Q R1 R1 wherein R is a tertiary cyclic amino radical selected from thegroup consisting of pyrrolidino, piperidino, morpholino,decahydroquinolino radicals, and lower-alkyl substituted pyrrolidino,piperidino, morpho'lino and decahydroquinolino radicals and R1 is amember selected from the group consisting of hydrogen and a lowerallcoxy radical, which includes the step of reacting at an elevatedtemperature and in the presence of an acidic condensing agent, anaromatic ketone of the formula:

OH 1 0 i ll OH-C wherein R1 is a member selected from the groupconsisting of hydrogen and a lower alkoxy radical, with a cyclicsecondary amine selected from the group consisting of pyrrolidine,piperidine, morpholine, decahydroquinoline, and lower-alkylsubstitutedpyrrolidines, piperidines, morpholines andtdecahydroquinolines, toobtain the corresponding desired tertiary N-desylamine.

2. A process for the preparation of tertiary N-desylamines of theformula:

' substituted pyrrolidino, piperi'dino, morpholino, anddecehydroquin-olin-o radicals and R1 is a member selected from the groupconsisting of hydrogen and a l-ower-alkoxy radical, which includes thesteps of reacting at an eleketone of the formula:

pentoxide an aromatic i i OH'O cyclic secondary amine selected from thegroup consisting of pyrrolidine, piper-idine, morpholine,dec'haydroquinoline, and lower-@alky-l substituted pyrrolidines,piperidines, morpholines and decahydroquinolines, to obtain thecorresponding desired tertiary Nedesylamin'e.

3; A process for the preparation ofN-di-*lower-alkoxydesylpyrrolidinewhich comprises reacting, at anelevated temperature and in the presence of a phosphorus pentoxide,pyrrolidine and an aromatic ketone of the formula:

P ii 011- 0 Q Q wherein R1 is a lower alkoxy radical, to torm thedesired N-di-lower-alkoxydesylpyrrolidine.

4. A process for the preparation of anN-di-lowerdialkoxydesylpyrrolidine which comprises reacting, at anelevated temperature and in the presence of an acidic condensing agent,pyrrolidine and an aromatic ketone of the formula:

v the desired N(para,para-dimethoxydesyl)-pyrrolidine.

vated temperature and in'the presence of phosphorus wherein R1 is amember selected from the group consisting of hydrogen and a lower-alkoxyradical, with a 7. A process for the preparation of N-desylpyrrolidinewhich comprises reacting, at an elevated temperature and in the presenceof phosphorus pentoxide, benzoin and pyrrolidine to form the desiredN-desylpyr rolidine.

-8. A process for the preparation ofN-(ortho,orth-odimethoxydesyl)-pyrrolidine which comprises reacting, atan elevated temperature and in the presence of phosphorus pent-oxide,ortho-anisoin and pyrrolidine to form the desiredN(ortho,orth0-dimethoxydesyl) -pyrrolid-ine.

9. A process for the preparation of N (meta,meta'- dimethoxydesyl)-pyr-ro-lidine which comprises reacting, at an elevated temperature andin the presence of phosphoruspentoxide, meta-anisoin and pyrrolidinetoform the desired N-(meta,meta-dimethoxydesyl)-pyrro1idine.

10. A process for the preparation of N-desyl-2-methylpyrrolidine whichcomprises reacting, at an elevated temperature, and in the presence ofphosphorus .pentoxide, benzoinland 2 methylpyrrolidine toN-desyl-Z-methYlpyrrolidine.

7 References Cited in the file of this patent FOREIGN PATENTS 667,356Germany Nov. 9, 1938 OTHER REFERENCES form the desired Germany Feb. 13,1939

1. A PROCESS FOR THE PREPARATION OF TERTIARY N-DESYLAMINES OF THE FORMULA: 